Loss of ADAMTS19 causes progressive non-syndromic heart valve disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE109247 | GEO | 2019/09/09
REPOSITORIES: GEO
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Project description:Valvular heart disease is observed in approximately 2% of the general population1. Although the initial observation is often localized (for example, to the aortic or mitral valve), disease manifestations are regularly observed in the other valves and patients frequently require surgery. Despite the high frequency of heart valve disease, only a handful of genes have so far been identified as the monogenic causes of disease2-7. Here we identify two consanguineous families, each with two affected family members presenting with progressive heart valve disease early in life. Whole-exome sequencing revealed homozygous, truncating nonsense alleles in ADAMTS19 in all four affected individuals. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype. Expression analysis using a lacZ reporter and single-cell RNA sequencing highlight Adamts19 as a novel marker for valvular interstitial cells; inference of gene regulatory networks in valvular interstitial cells positions Adamts19 in a highly discriminatory network driven by the transcription factor lymphoid enhancer-binding factor 1 downstream of the Wnt signaling pathway. Upregulation of endocardial Krüppel-like factor 2 in Adamts19 knockout mice precedes hemodynamic perturbation, showing that a tight balance in the Wnt-Adamts19-Klf2 axis is required for proper valve maturation and maintenance.
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Project description:Loss of ADAMTS19 causes progressive non-syndromic heart valve disease
| PRJNA430237 | ENA
Project description:We use single cell RNA-sequencing (Drop-seq) to profile cardiac cells (excluded atria) from control (Wt1 CreERT2/+; Rosa26mTmG/+) and epicardial-deficient Lats1/2 kinase embryonic hearts (Wt1 CreERT2/+; Lats1/2 F/F; Rosa26mTmG/+) at E13.5 and E14.5. Each experimental group includes cells sampled from four embryonic hearts.
2018-04-23 | GSE100861 | GEO
Project description:Background: To better understand the role DNA methylation plays in regulating gene expression in the developng heart and furthermore the role it plays in heart development we performed genome wide DNA methylation profiling of embryonic hearts at embryonic day (E)11.5 and E14.5 using methyl sensitive tiny fragment enrichment coupled with massive parallel sequencing by using the methyl-sensitive restriction enzyme HpyCH4IV, recognition site 'ACGT'. Results: We found that global methylation remains stable at analyzed 'ACGT' sites (1.64 million site) in developing hearts between E11.5 and E14.5. However, differential methylation was identified at individual loci enriched at genes involved in heart development suggesting a role for DNA methylation in the developing heart. Used Methyl Sensitive Tiny Fragment Enrichment/Massive Parallel Sequencing (MSFE/MPS) to assay methylation at 'ACGT' sites throughout the genome and generate a developmental profile of DNA methylation in the embryonic heart and to identify differences between developing mouse hearts at E11.5 and E14.5.
2014-06-27 | E-GEOD-55141 | biostudies-arrayexpress
Project description:ObjectiveNormal adipose tissue growth and function is critical to maintaining metabolic homeostasis and its excess (e.g. obesity) or absence (e.g. lipodystrophy) is associated with severe metabolic disease. The goal of this study was to understand the mechanisms maintaining healthy adipose tissue growth and function.MethodsAdipose tissue senses and responds to systemic changes in growth factor and nutrient availability; in cells mTORC1 regulates metabolism in response to growth factors and nutrients. Thus, mTORC1 is poised to be a critical intracellular regulator of adipocyte metabolism. Here, we investigate the role of mTORC1 in mature adipocytes by generating and characterizing mice in which the Adiponectin-Cre driver is used to delete floxed alleles of Raptor, which encodes an essential regulatory subunit of mTORC1.ResultsRaptor (Adipoq-cre) mice have normal white adipose tissue (WAT) mass for the first few weeks of life, but soon thereafter develop lipodystrophy associated with hepatomegaly, hepatic steatosis, and insulin intolerance. Raptor (Adipoq-cre) mice are also resistant to becoming obese when consuming a high fat diet (HFD). Resistance to obesity does not appear to be due to increased energy expenditure, but rather from failed adipose tissue expansion resulting in severe hepatomegaly associated with hyperphagia and defective dietary lipid absorption. Deleting Raptor in WAT also decreases C/EBP? expression and the expression of its downstream target adiponectin, providing one possible mechanism of mTORC1 function in WAT.ConclusionsmTORC1 activity in mature adipocytes is essential for maintaining normal adipose tissue growth and its selective loss in mature adipocytes leads to a progressive lipodystrophy disorder and systemic metabolic disease that shares many of the hallmarks of human congenital generalized lipodystrophy.
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Project description:AimsMyxomatous valve disease (MVD) is the most common aetiology of primary mitral regurgitation. Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults. Wnt/?-catenin signalling is active during heart valve development and has been reported in human MVD. The consequences of increased Wnt/?-catenin signalling due to Axin2 deficiency in postnatal valve remodelling and pathogenesis of MVD were determined.Methods and resultsTo investigate the role of Wnt/?-catenin signalling, we analysed heart valves from mice deficient in Axin2 (KO), a negative regulator of Wnt/?-catenin signalling. Axin2 KO mice display enlarged mitral and aortic valves (AoV) after birth with increased Wnt/?-catenin signalling and cell proliferation, whereas Sox9 expression and collagen deposition are decreased. At 2 months in Axin2 KO mice, the valve extracellular matrix (ECM) is stratified but distal AoV leaflets remain thickened and develop aortic insufficiency. Progressive myxomatous degeneration is apparent at 4 months with extensive ECM remodelling and focal aggrecan-rich areas, along with increased BMP signalling. Infiltration of inflammatory cells is also observed in Axin2 KO AoV prior to ECM remodelling. Overall, these features are consistent with the progression of human MVD. Finally, Axin2 expression is decreased and Wnt/?-catenin signalling is increased in myxomatous mitral valves in a murine model of Marfan syndrome, supporting the importance of Wnt/?-catenin signalling in the development of MVD.ConclusionsAltogether, these data indicate that Axin2 limits Wnt/?-catenin signalling after birth and allows proper heart valve maturation. Moreover, dysregulation of Wnt/?-catenin signalling resulting from loss of Axin2 leads to progressive MVD.
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Project description:We report changes in the levels of gene expression between 48hpf hearts and 56hpf hearts, the initial stages of valvulogenesis
2016-04-15 | GSE79585 | GEO
Project description:Background: To better understand the role DNA methylation plays in regulating gene expression in the developng heart and furthermore the role it plays in heart development we performed genome wide DNA methylation profiling of embryonic hearts at embryonic day (E)11.5 and E14.5 using methyl sensitive tiny fragment enrichment coupled with massive parallel sequencing by using the methyl-sensitive restriction enzyme HpyCH4IV, recognition site 'ACGT'. Results: We found that global methylation remains stable at analyzed 'ACGT' sites (1.64 million site) in developing hearts between E11.5 and E14.5. However, differential methylation was identified at individual loci enriched at genes involved in heart development suggesting a role for DNA methylation in the developing heart.
2014-06-27 | GSE55141 | GEO
Project description:Purpose: The goals of this study are to characterize and analyze the emrbyonic heart transcriptome profiling (RNA-seq) at E9.5, E10.5, E12.5, E14.5 and E16.5. Methods: mRNA profiles of E9.5, E10.5, E12.5, E14.5 and E16.5 C57/Bl6 mouse embryonic hearts were generated by deep sequencing, n=3 or 4 for each age, using Illumina HiSeq2500. Results: Using an optimized data analysis workflow, we mapped at least 36 million sequence reads per sample to the mouse genome (build mm10) and identified 17,537 transcripts in the mouse hearts.
2023-04-07 | GSE223237 | GEO
Project description:Myocardial left ventricular biopsies from male patients (n=6) with isolated aortic stenosis and pronounced left ventricular hypertrophy undergoing aortic valve replacement were harvested either from hearts with normal ejection fraction (EF,>50%) or with low EF (<30%). Biopsies were further obtained from non-hypertrophied hearts with normal EF (>60%) from coronary artery disease patients undergoing coronary artery bypass graft surgery (n=3). Total RNA isolated from biopsies was analyzed using Affymetrix HG-U133A and U133B GeneChip sets.
2010-12-15 | E-MEXP-2296 | biostudies-arrayexpress